The method presently available for solid-phase synthesis of C-terminal peptide N-substituted amides, such as N-ethylamide, using N.sup..alpha. Boc and the usual side-chain-protecting groups, involves cleavage of a benzyl ester resin linkage by aminolysis using ethylamine. Following removal of excess ethylamine and separation from the resin, the protected peptide is deprotected using hydrogen fluoride(HF) and then purified via several steps. The method is inapplicable to peptides containing either Asp or Glu, protected as the benzyl ester, because these side chains will also undergo aminolysis. Thus, it has been heretofore necessary to synthesize such N-substituted peptides using classical synthesis or using some other suitable synthesis.
N-methyl amidated peptides have been successfully synthesized on an N-methyl benzhydrylamine resin, Rivier, J. et al., J. Med. Chem. 20, 1409 (1977); however, N-ethyl amidated peptides could not be successfully synthesized using the corresponding ethyl-substituted resin. Accordingly, improved methods for the solid-phase synthesis of N-substituted peptide amides were sought after.